WO2003015784A1 - 1-arylpiperazines substituees en 2 antagonistes de la tachykinine et/ou des inhibiteurs de la recapture de la serotonine - Google Patents

1-arylpiperazines substituees en 2 antagonistes de la tachykinine et/ou des inhibiteurs de la recapture de la serotonine Download PDF

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WO2003015784A1
WO2003015784A1 PCT/EP2002/009066 EP0209066W WO03015784A1 WO 2003015784 A1 WO2003015784 A1 WO 2003015784A1 EP 0209066 W EP0209066 W EP 0209066W WO 03015784 A1 WO03015784 A1 WO 03015784A1
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solution
piperazine
phenyl
acoet
carboxylic acid
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Guiseppe Alvaro
Torquil Iain Maclean Jack
Maria Elvira Tranquillini
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority to DE60206781T priority Critical patent/DE60206781T2/de
Priority to EP02794786A priority patent/EP1423117B1/fr
Priority to US10/486,479 priority patent/US7214680B2/en
Priority to JP2003520743A priority patent/JP2005502655A/ja
Priority to AT02794786T priority patent/ATE306924T1/de
Publication of WO2003015784A1 publication Critical patent/WO2003015784A1/fr
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to N-phenyl piperazine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use.
  • USP 5880128 and WO 9631501 disclose interalia N'-carbonyl-N aryl piperazine derivatives which inhibit farnesylprotein transferase.
  • WO 9846626 and WO 9846627 disclose some N-phenyl-N' substituted piperazine derivatives as factor Xa inhibitors. Such compounds are useful as inhibitors of blood coagulation in mammalian species.
  • WO 9525443 describes certain N-phenyl-N' substituted piperazine derivatives useful as oxytocin or vasopressin antagonists.
  • R represents halogen, C ⁇ alkyl, trifluoromethoxy or trifluoromethyl
  • Rj is trifluoromethyl, C ⁇ __ alkyl, C ⁇ __ ⁇ alkoxy, halogen or trifluoromethoxy;
  • R2 is hydrogen, C ⁇ ._ alkyl or C2-6 alkenyl
  • R3 represents hydrogen or C ⁇ __ ⁇ alkyl; n and m are independently 0 or an integer from 1 to 3; and pharmaceutically acceptable salts and solvates thereof.
  • a further embodiment of the invention provides compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein R represents halogen or C ⁇ __ alkyl;
  • R ⁇ is trifluoromethyl, C ⁇ __ ⁇ alkyl, C ⁇ __ alkoxy, halogen or trifluoromethoxy;
  • R2 is hydrogen, C ⁇ __ alkyl or C2-6 alkenyl;
  • R3 represents hydrogen or Cj ⁇ j. alkyl;
  • n and m are independently 0 or an integer from 1 to 3;
  • Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, trifluoroacetates, lactates, fumarates, malates and maleates.
  • pharmaceutically acceptable organic or inorganic acids for example hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, trifluoroacetates, lactates, fumarates, malates and maleates.
  • the solvates may, for example, be hydrates.
  • references hereinafter to a compound according to the invention include both compounds of formula (1) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates.
  • the wedge shaped bond indicates that the bond is above the plane of the paper.
  • the broken bond indicates that the bond is below the plane of the paper.
  • the configuration shown for the chiral carbon atom indicated as * in formula la is ⁇ and in formula lb is ⁇
  • the ⁇ configuration at the chiral carbon atom indicated as * corresponds to the S isomer and the ⁇ configuration corresponds to the R isomer.
  • asymmetric carbon atoms are possible in the compound of formula (T).
  • R2 is C ⁇ _4 alkyl or C2_6 alkenyl
  • the compounds of formula (f) possess at least two asymmetric carbon atoms.
  • the assignment of the R and S configuration of the asymmetric carbon atoms of the compounds of the invention has been made according to the rules of Cahn, Ingold and Prelog 1956, 12, 81.
  • crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited in formulas I and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3 H, n C, U C, 18 F, 123 I and 125 I.
  • Isotopically - labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • U C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 125 I are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • C ⁇ __ alkyl as used herein as a group or a part of the group refers to a straight or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert butyl.
  • C 2-6 alkenyl as used herein refers to a straight or branched alkenyl group containing from 2 to 6 carbon atoms examples of such groups include vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, hexenyl and the like.
  • C ⁇ __ alkoxy refers to a straight or branched alkyl group containing from 1 to 4 carbon atoms attached to an oxigen atom; examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert butoxy.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • R represents halogen this is suitably chlorine or more preferably fluorine or when R is C ⁇ __ alkyl this is suitably methyl.
  • each of the two or three groups R may be the same or different.
  • each of the two or three Regroups may be the same or different.
  • Suitable values for R ⁇ include trifluoromethyl or halogen.
  • Suitable values for R2 and R3 include hydrogen or methyl.
  • n is preferably 2.
  • a preferred class of compound of formula(T) are those wherein R is selected from trifluromethyl, methyl or halogen,(e.g fluorine), R ⁇ is trifluoromethyl or halogen, R3 is methyl, R2 is methyl or hydrogen and n is 2.
  • Preferred compounds according to the invention are:
  • (+/-)l-(4-Fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid [l-(3,5-dichloro-phenyl)- ethyl]-methylamide
  • (+/-)l-(4-Fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid (3,5-dichloro-benzyl)- (+/- methylamide
  • (+/-)l-(4-Fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid (3,5-bis-trifluoromethyl- benzyl)-methylamide
  • (+/-) 1 -(4-Fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid (3,4-dibromo-benzyl)- methylamide
  • (+/-)l-(4-Trifluoromethyl-phenyl)-piperazine-2-carboxylic acid (3,5-bis-trifluoromethyl- benzyl)-methylamide; and enantiomers, diastereoisomers, pharmaceutically acceptable salts (e.g. hydrochloride) and solvates thereof.
  • the compounds of the invention are antagonists of tachykinin receptors, including substance P and other neurokinins, both in vitro and in vivo and are thus of use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins.
  • Tachykinins are a family of peptides that share a common carboxyl-terminal sequence (Phe- X-Gly-Leu-Met-NH2). They are actively involved in the physiology of both lower and advanced lifeforms. In mammalian lifeforms the main tachykinins are subtance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmitters and neuromodulators. Mammalian tachykinins may contribute to the pathophysiology of a number of human diseases.
  • SP subtance P
  • NKA Neurokinin A
  • NKB Neurokinin B
  • NKl Three types of tachykinins receptors have been identified, namely NKl(SP-preferring), NK2 (NKA-preferring) and NK3 (NKB-preferring) which are widely distributed throughout the central nervous (CNS) and peripheral nervous system.
  • the compounds of the invention are antagonists of the NK1 receptor.
  • the compounds of the present invention also have activity as selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) and are thus of use in the treatment of conditions mediated by selective inhibition of the serotonin reuptake transporter protein.
  • SSRIs selective serotonin reuptake inhibitors
  • the compounds of the present invention combine dual activity as tachykinin antagonists, including substance P and other neurokinins, and as SSRIs.
  • the compounds of the invention combine dual activity as NK1 receptor antagonists and as SSRIs.
  • this dual NKI and SSRIs activity may in certain cases be exhibited by isomeric mixtures, including racemic mixtures or by individual stereoisomers comprised in a stereoisomeric mixture.
  • the relative level of NKI and SSRIs activity in vitro or in vivo, may differ between individual stereoisomers of a stereisomeric mixture.
  • individual stereoisomers may exibit synergy when present in combination as a stereoisomeric mixture i.e the individual levels of NKI and SSRIs activity of a stereisomeric mixture may be greater than -the level of activity associated with individual stereoisomers comprised in the stereisomeric mixture.
  • the enantiomers comprising a racemic mixture may exhibit synergy such that the levels of NKland SSRIs activity of the racemate are higher than the individual levels of NKland SSRIs activity of the individual enantiomers.
  • the compounds of the present invention are particularly useful for the treatment of of CNS disorders and psychotic disorders, in particular in the treatment or prevention of depressive states and /or in the treatment of anxiety.
  • NKi-receptor binding affinity has been determined in vitro by measuring the compounds' ability to displace [3H] - substance P (SP) from recombinant human NKj receptors expressed in Chinese Hamster Ovary (CHO) cell membranes.
  • SP substance P
  • CHO cell membranes were prepared by using a modification of the method described by Beattie D.T. et al. (Br. J. Pharmacol, 116:3149-3157, 1995). Briefly, ligand binding was performed in 0.2 ml of 50 mM HEPES, pH 7.4, containing 3 mM MnCl 2 , 0.02% BSA, 0.5 nM [ 3 H]-Substance P (30 ⁇ 56 Ci/mmol, Amersham), a final membrane concentration of 20 ⁇ 30 ⁇ g of protein/ml, and the test compounds. The incubation proceeded at room temperature for 40 min and stopped by filtration. Non-specific binding was determined using excess of Substance P (1 ⁇ M) and represents about 6 ⁇ 10% of the total binding.
  • Compounds of the invention were further characterised in a functional assay for the determination of their effect to inhibit the intracellular calcium increase induced by SP in Human-NKj-CHO cells using FLIPR technology. Briefly, after 30min incubation with the cytoplasmic calcium indicator Fluo-4 AM (2 ⁇ M), cells were washed and incubated in the absence or presence of three different concentrations of antagonist for 60min, at 37°C in Hank's balanced salts with 20mM Hepes, and then non-cumulative concentration-response curves of SP (2pM-300nM) was performed. The potency of the antagonist (pK B value) was calculated from Schild's analysis.
  • the action of the compounds of the invention at the NKi receptor and/or serotonin transporter may be determined by using conventional animal models.
  • the ability to bind at the NKj receptor and/or serotonin transporter was determined using the guinea pig pup isolation calls model as described by Pettijohn, Psychol. Rep., 1979 and Rupniak et al., Neuropharmacology, 2000.
  • Human Serotonin Transporter (hSERT) binding affinity has been determined in vitro by the compounds' ability to displace [ 3 H]- Irnipramine from human serotonin transporter expressed in Human Embryonic Kidney HEK293 cell membranes (Receptor Biology Inc.).
  • Human Serotonin Transporter binding affinity has been also determined in vitro by the compounds ability to displace [3H] paroxetine. Competition experiments were conducted with duplicate determination for each point. Msat601 software package was used to elaborate the competition binding data. IC 50 values were converted to Kf values using Cheng-Prusoff equation.
  • the inhibitory activity of the compounds at the rat serotonin transporter has been determined in vitro using rSERT-LLCPK cells (LLCPK cells tranfected with the rat SERT). The cells have been plated onto 96-well plates (60000 cells/well). After 24 hr, cells have been washed in uptake buffer (Hank's balanced salt solution + 20 mM Hepes) and pre-incubated for 10 min at RT with 50 ⁇ l of buffer containing the test compounds. 50 ⁇ l of 50 nM [3H] Serotonin
  • 5HT solution (final concentration: 25 nM [3H] 5HT) have been added and plates have been incubated for 7 min at RT, during which cells take up radiolabelled 5HT. Aspirating the solution and rapidly washing the cells with cold buffer has terminated the uptake.
  • the amount of radioactive 5HT incorporated in the cells has been then measured by adding the scintillation cocktail directly onto the cells and reading the plate in the Top Count.
  • the data have been digitally processed to obtain the pIC50 values of the antagonists.
  • the pKi values have been calculated using the Chen-Prusoff equation.
  • Compounds of the invention are useful in the treatment of CNS disorders and psychotic disorders, in particular in the treatment or prevention of depressive states and /or in the treatment of anxiety as defined in, but not restricted to, Diagnostic Statistical of mental disorder (DSM) IV edition edit by American Psychiatric association and international classification Diseases 10 th revision ( ICD10) .
  • DSM Diagnostic Statistical of mental disorder
  • depressive states include Major Depressive Disorder (MDD), including bipolar depression, unipolar depression, single or recurrent major depressive episodes , recurrent brief depression, with or without psychotic features, catatonic features, melancholic features including anorexia, weight loss, atypical features, anxious depression, cyclothymic or postpartum onset.
  • MDD Major Depressive Disorder
  • Major depressive disorders include dysthymic disorder with early or late onset and with or without atypical features, neurotic depression, post traumatic stress disorders and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood.
  • Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc.
  • anxiety includes anxiety disorders, such as panic disorders with or without agoraphobia, agoraphobia , phobias for example social phobias or agoraphobia, obsessive- compulsive disorder, stress disorders including post traumatic stress disorder generalised anxiety disorder , acute stress disorders and mixed anxiety-depression disorders.
  • Compounds of the invention are useful as analgesics.
  • traumatic pain such as postoperative pain
  • traumatic avulsion pain such as brachial plexus
  • chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis
  • neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, f ⁇ bromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain
  • various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrap
  • Compounds of the invention are also useful in the treatment of sleep disorders including dysomnia, insomnia, sleep apnea, narcolepsy, and circadianrudic disorders.
  • Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified.
  • compounds of the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit.
  • Compounds of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of dependence on nicotine, alcohol, caffeine, phencyclidine (phencyclidine like compounds), or in the treatment of tolerance to and dependence on opiates (e.g. cannabis, heroin, morphine) or benzodiazepines; in the treatment of cocaine, sedative ipnotic, amphetamine or amphetamine- related drugs (e.g. dextroamphetamine, methylamphetamine) addiction or a combination thereof.
  • Compounds of the invention are also useful as anti-inflammatory agents.
  • Compounds of the invention are also useful in the treatment of allergic disorders,' in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.
  • Compounds of the invention are also useful in the treatment or prevention of schizophrenic disorders including paranoid schizophrenia, disorganised schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia.
  • Emesis i.e. nausea, retching and vomiting.
  • Emesis includes acute emesis, delayed emesis and anticipatory emesis.
  • the compounds of the invention are useful in the treatment of emesis however induced.
  • emesis may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g, cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g.
  • cytarabine methotrexate and 5- fluorouracil
  • vinca alkaloids e.g. etoposide, vinblastine and vincristine
  • others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof
  • radiation sickness e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g.
  • gastritis or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease, acid indigestion, overindulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.
  • vestibular disorders such as motion sickness, vertigo, dizziness and Meniere's disease
  • gastrointestinal obstruction reduced gastrointestinal motility
  • visceral pain e.g. myocardial infarction or peritonitis
  • migraine e.
  • Compounds of the invention are also useful in the treatment of gastrointestinal disorders such as irritable bowel syndrome; skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.
  • the compounds of the invention are also useful in premenstrual dysphoric disorder (PMDD), in chronic fatigue syndrome_and Multiple sclerosis.
  • PMDD premenstrual dysphoric disorder
  • the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.
  • a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions mediated by tachykinins (including substance P and other neurokinins) and/or by selective inhibition of serotonin reuptake.
  • a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the treatment of conditions mediated by tachykinins (including substance P and other neurokinins) and/or by selective inhibition of the serotonin reuptake transporter protein.
  • tachykinins including substance P and other neurokinins
  • selective inhibition of the serotonin reuptake transporter protein Li a further aspect there is provided the use of a compounds of formula(T) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of depression and /or anxiety.
  • a method for the treatment of a mammal including man, in particular in the treatment of depression and /or anxiety which method comprises administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • compositions which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof and formulated for administration by any convenient route.
  • Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution -with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • composition may take the form of tablets or formulated in conventional manner.
  • the compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or nonaqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • a proposed dose of the compounds of the invention is 1 to about lOOOmg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian.
  • the dosage will also depend on the route of administration and the particular compound selected. Thus for parenteral administration a daily dose will typically be in the range of 1 to about 100 mg, preferably 1 to 80 mg per day. For oral administration a daily dose will typically be within the range 1 to 300 mg e.g. 1 to 100 mg.
  • a compound of formula (I) may be prepared by reaction of an activated derivative of the carboxylic acid of formula (H), wherein R a is a suitable nitrogen protecting group, with amine (T ⁇ ) or salts thereof, optionally in the presence of a suitable base, followed by removal of the protecting group R a ,
  • Suitable activated derivatives of the carboxyl group include the corresponding acyl halide, mixed anhydride, activated ester such as a thioester or a derivative formed between the carboxylic acid group and a coupling agent such as that used in peptide chemistry, for example O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate.
  • the reaction is preferably carried out in an aprotic solvent such as an ether, e.g. tetrahydrofuran, a halohydrocarbon, e.g. dichloromethane, N,N-dimethylformamide or acetonitrile.
  • an aprotic solvent such as an ether, e.g. tetrahydrofuran, a halohydrocarbon, e.g. dichloromethane, N,N-dimethylformamide or acetonitrile.
  • Suitable base for use in this reaction include organic base such as triethylamine or N,N diisopropylethylamine.
  • the activated derivatives of the carboxylic acid (H) may be prepared by conventional means.
  • a particularly suitable activated derivative for use in this reaction is obatained by reaction of the carboxylic acid (H) with O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, a halohydrocarbon e.g. dichloromethane, an amide e.g. N,N-dimethylformamide or acetonitrile.
  • a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, a halohydrocarbon e.g. dichloromethane, an amide e.g. N,N-dimethylformamide or acetonitrile.
  • L is a suitable leaving group such as halogen (e.g. chlorine, bromine or iodine) and Rb is an appropriate group capable to be converted into the carboxylic group, followed by conversion of Rb into the carboxylic group.
  • halogen e.g. chlorine, bromine or iodine
  • Suitable Rb groups for use in this reaction include a carboxyl protected group or a cyano group.
  • the reaction conveniently takes place in an aprotic solvent such as a hydrocarbon (e.g. toluene) optionally in the presence of a base such as a tertiary amine (e.g. diisopropylethylamine) and preferably with heating e.g. 40°-120°C.
  • aprotic solvent such as a hydrocarbon (e.g. toluene)
  • a base such as a tertiary amine (e.g. diisopropylethylamine) and preferably with heating e.g. 40°-120°C.
  • Rb is a carboxyl protected group
  • suitable groups includes allyloxycarbonyl, alkyloxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t- butyloxycarbonyl) arylmethyloxycarbonyl (e.g. benzyloxycarbonyl or p- nitrobenzyloxycarbonyl) and the like.
  • Rb is a carboxyl protected group
  • the conversion into carboxylic acid may be carried out using known procedure for removing carboxylic protecting groups.
  • Rb is methoxycarbonyl or ethoxycarbonyl
  • the conversion into carboxylic group may be carried out by alkaline hydrolysis using, for example, sodium hydroxide or lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol e.g. methanol or isopropanol.
  • Rb is a cyano group
  • the conversion into the carboxylic group may be carried out by reduction of the cyano group with lithium aluminum hydride.
  • An appropriate reducing agent for this reaction includes for example borane or a borohydride, e.g. sodium borohydride, sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.
  • a borohydride e.g. sodium borohydride, sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.
  • the reaction conveniently takes place in a suitable solvent such as alcohol (i.e. ethanol or methanol) at a temperature ranging between room temperature and reflux temperature.
  • a suitable solvent such as alcohol (i.e. ethanol or methanol) at a temperature ranging between room temperature and reflux temperature.
  • a compound of formula (VI) may be prepared by alkylation of a compound of formula (VTf), wherein R a represents a nitrogen protecting group and L is a leaving group as defined above, with amine (VET).
  • the reaction may be carried out in an aprotic solvent such as dichloromethane or alkyl esters (e.g. ethylacetate) and in the presence of an organic base such as triethylamine.
  • an aprotic solvent such as dichloromethane or alkyl esters (e.g. ethylacetate)
  • an organic base such as triethylamine.
  • R a is a nitrogen protecting group
  • suitable groups include alkoxycarbonyl e.g. t-butoxycarbonyl, benzyloxycarbonyl, arylsulphonyl e.g. phenylsulphonyl, arylmethyl e.g benzyl or 2-trimethylsilylethoxymethyl. Protection and deprotection may be effected using conventional techniques such as those described in "Protective Groups in Organic Synthesis 2 nd Ed.” by T.W. Greene and P. G. M. Wuts (John Wiley and Sons, 1991) and as described in the examples hereinafter.
  • R a is a benzyl group
  • this may be removed by hydrogenation in a suitable solvent such as ethanol or methanol or by hydrolysis in the presence of haloformiates such as for example chloroformiates and in the presence of a suitable organic base.
  • compound of formula (IV) may be prepared by reaction of a compound of formula(LX), wherein L is a suitable leaving group such as halogen (i.e chlorine or bromine) or mesilate, with NH2Ra wherein Ra is a suitable nitrogen protecting group.
  • L is a suitable leaving group such as halogen (i.e chlorine or bromine) or mesilate
  • NH2Ra wherein Ra is a suitable nitrogen protecting group
  • the reaction conveniently takes place in an aprotic solvent such as an aprotic solvent optionally in the presence of a base such as a tertiary amine and preferably with heating e.g. 40°-120°C.
  • an aprotic solvent such as an aprotic solvent optionally in the presence of a base such as a tertiary amine and preferably with heating e.g. 40°-120°C.
  • compounds of formula (LX) may be prepared according to the preparation described in Tulyaganov, S. R. and Khasanov, S. A, Uzb. Khim. Zh. (1971), 15(2), 62-4) or Sineokov, A. et al., Zh. Org. Khim. (1968), 4(2), 284-7.
  • the compounds of formula (I) may be readily isolated in association with solvent molecules by crystallisation from or evaporation of an appropriate solvent to give the corresponding solvates.
  • specific enantiomers of the compounds of formula (I) may be prepared by reaction of a suitable chiral alcohol, in the presence of a source of a carbonyl group (such as triphosgene or carbonyl diimidazole) separating the resulting diastereoisomeric carbamates by conventional means, e.g. chromatography or by fractional crystallisation.
  • a source of a carbonyl group such as triphosgene or carbonyl diimidazole
  • the required enantiomer of a compound of general formula (I) may be isolated by removal of carbamate and conversion into the required free base or salts thereof.
  • Suitable chiral alcohols for use in the process include (R)-,sec-phenylethyl alcohol.
  • the required enantiomer may be obtained from racemic compounds of formula (I) by use of Corpal HPLC procedures.
  • enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.
  • the required enantiomer may be prepared by the corresponding enantiomeric acid of formula (H) using any of the process described above for preparing compounds of formula (I) from the acid (D).
  • the single enantiomer of acid (ffl) may be prepared from the racemic acid (EL) using conventional procedures such as salt formation with a suitable optically active amine, such as (R)- ⁇ -phenylethylamine, (S)- ⁇ -phenylethylamine, brucine, cinconidine, quinine, followed by separation of the two diasteroisomer salts obtained and regeneration of the free acid.
  • a suitable optically active amine such as (R)- ⁇ -phenylethylamine, (S)- ⁇ -phenylethylamine, brucine, cinconidine, quinine
  • the two diasteroisomer salts may be conveniently separated by conventional means such as fractionally crystallisation or by chromatography.
  • Li a further embodiment of the invention the specific enantiomer of acid (H) may by prepared by esterification of racemic acid (H) with a suitable optically active alchool, separating the resulting diastereoisomeric esters by conventional means e.g. chromatography, followed by hydrolysis of the required single diastereomeric ester.
  • Suitable chirals alcohols for use in this process include S(+)-indanol, S(+)methylmandelate, S(-) methyl lactate or R(+) t-butyl lactate.
  • the diastereoisomeric esters of a compound of formula (IT) may be prepared by conventional means such as reaction of the chiral alcohol with an activated derivative of a compound of formula (H) in an aprotic solvent such as ether e.g. tetrahydrofuran.
  • the activated derivative of a compound of formula (H) may be prepared from a compound of formula (H) using conventional means for preparing activated derivatives of a carboxylic acid groups such as those conveniently used in peptide synthesis.
  • a convenient method of preparing the diastereoisomeric esters of a compound of formula (H) is to prepare the activated derivative of a compound of formula (II) in the presence of the chiral alcohol.
  • a compound of formula (IT) may be treated with the Mitsunobu combination of reagents, i.e. a dialkylazo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphine e.g. triphenylphosphine in the presence of the chiral alcohol.
  • the reaction conveniently takes place in the presence of a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof, at a temperature ranging from 0 -30°C.
  • a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof, at a temperature ranging from 0 -30°C.
  • the required single diastereoisomeric ester of a compound of formula ( ⁇ ) substantially free of the other diastereoisomers may be obtained from the mixture thereof by conventional means, for example by the use of conventional chromatographic procedures such as preparative HPLC or by fractional crystallization.
  • the required enantiomer may be prepared from the corresponding single diastereoisomeric ester of a compound of formula (I) by hydrolysis, e.g. alkaline hydrolysis.
  • the hydrolysis may be carried using an alkali metal hydroxide e.g. sodium hydroxide or lithium hydroxide in a solvent such as an ether, e.g. tetrahydrofuran, and water.
  • Physiologically acceptable salts of compounds of formula (I) may be prepared by treating the corresponding base with an appropriate acid in a suitable solvent.
  • salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compound of formula (I) using conventional methods In the Intermediates and Examples unless otherwise stated:
  • Enantiomer 1, enantiomer 2, diastereoisomer 1 or diastereoisomer 2 refer to a single enantiomer or a single diasteroisomer respectively, whose absolute stereochemistry was not characterised .
  • Diastereoisomer A or diastereoisomer B refer to a mixture of two diastereoisomers whose absolute stereochemistry was not characterised .
  • the X-ray powder diffraction pattern of a crystalline form of the compounds of the invention was obtained by loading the sample into the diffractometer (Siemens D5005 X-ray diffractometer equipped with ⁇ / ⁇ goniometer, scintillation counter and graphite monochromator.
  • the diffractometer was set up with the instrumental parameters given below:
  • MONOCHROMATIC RADIATION Cu - 1.54056/1.54439
  • DIPEA 225 ⁇ L
  • O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate 175 mg
  • a solution of intermediate 15 140 mg
  • anhydrous DMF 10 mL
  • 3,5-dicWoro-benzyl-methylamine hydrochloride 103 mg was added and the mixture was stirred at r.t. for 4.5 hours.
  • the solution was diluted with water (5 mL) and extracted with AcOEt (3 x 30 mL).
  • DIPEA (0.34 mL) and O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate (257 mg) were added to a solution of intermediate 8 (214 mg) in anhydrous DMF (35 mL) under a Nitrogen atmosphere. After stirring for 5 minutes, 3,5-dibromo-ber ⁇ zyl-methylamine hydrochloride (300 mg) was added and the mixture was stirred at r.t. overnight. The solution was diluted with water and extracted with AcOEt (3 x 40 mL).
  • DIPEA 0.1 mL
  • O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate 74 mg
  • a solution of intermediate 8 61 mg
  • anhydrous DMF 10 mL
  • 3,4-dibromo-benzyl-methylamine hydrochloride 85.4 mg was added and the mixture was stirred at r.t. overnight.
  • the solution was diluted with water and extracted three times with AcOEt.
  • Tic AcOEt/CH 1:1, RfM).71.
  • DIPEA 80 ⁇ L
  • O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate 60 mg
  • a solution of intermediate 8 50 mg
  • anhydrous DMF 5 mL
  • 2,5-dichloro-benzyl-methylamine hydrochloride 35 mg was added and the mixture was stirred at r.t. for 5 hours.
  • the solution was partitioned between AcOEt and water.
  • DIPEA 80 ⁇ L
  • O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate 60 mg
  • intermediate 8 50 mg
  • anhydrous DMF 5 mL
  • Nitrogen atmosphere After stirring for 5 minutes, (3-fluoro-5-trifluoromethyl)-benzylamine (30 mg) was added and the mixture was stirred at r.t. overnight.
  • the solution was partitioned between AcOEt and water.
  • DIPEA (0.13 mL) and O-(benzotriazol-l-yl)-N,N,N'N'-tetramethyluronium tetrafluoroborate (73 mg) were added to a solution of intermediate 33 (60 mg) in anhydrous DMF (7 mL) under a Nitrogen atmosphere. After stirring for 5 minutes, 3,5-bis(trifluoromethyl)-benzyl- methylamine hydrochloride (55 mg) was added and the mixture was stirred at r.t. for 5 hours. The solution was partitioned between AcOEt and water. The separated aqueous phase was further extracted with AcOEt.
  • N-Benzyl-2-(2,4,6-trifluoro-phepyIamino)-acetamide A mixture of N-benzyl-2-chloroacetamide (700 mg - obtained as described for intermediate 1), DIPEA (0.76 mL) and 2,4,6-trifluoro-aniline (559 mg) in anhydrous DMF (5 mL) was stirred at 100°C for 40 hours under a Nitrogen atmosphere. Then, more DIPEA (0.2 mL) was added and the mixture was heated to 100°C for further 4 hours. After cooling to room temperature, the solution was diluted with AcOEt and washed with water and ice. The separated aqueous phase was extracted with further AcOEt (3 x 30 mL).
  • (+/-) l-(4-Fluoro-2-methvI-phenyl)-piperazine-2-carboxylic acid (3,5-bis- trifluoromethyl-benzylVmethylamide hydrochloride
  • EtOH 85 mL
  • glacial acetic acid 0.28 mL
  • 10% palladium on carbon
  • Method B The compound of Example 2a (700 mg) was dissolved in anhydrous Et2O (15 mL) and treated at 0°C with hydrochloric acid (IM in Et2O - 1.87 mL). The mixture was stirred at 0°C for 30 minutes, then concentrated in vacuo. The residue was triturated with pentane (3 x 5 mL) to give the title compound (735 mg) as an off-white solid. M.p.: 110-113°C.
  • DIPEA (0.48 mL) was added to the solution of intermediate 9a in AcOEt (6 mL) at room temperature.
  • 1-chloroethyl chloroformiate (0.44 mL) was dropped over 15 minutes.
  • the resulting solution was stirred at room temperature over 2 hours then IN hydrochloric acid (5.5 mL) was added and the reaction was heated at 60°C for 2 hours.
  • the organic mixture was cooled to room temperature then isooctane (10 mL) and MeOH (2 mL) were added. The the two phases were separated and the aqueous one was washed again with isooctane/AcOEt 2/1(8 mL).
  • Example 5b The compound of Example 5b (192 mg) was dissolved in anhydrous Et2O (10 mL) and treated at 0°C with hydrochloric acid (IM in Et2O - 0.515 mL). The mixture was stirred at 0°C for 30 minutes, then concentrated in vacuo. The residue was washed with pentane (2 x 2 mL) to give the title compound (200 mg) as an off-white solid.
  • Example 3 ( 75.5 mg )and example 4 (25.6 mg) were mixed to give enriched mixtures 75:25 to give the title compound.
  • Example 3(25.2 mg) and Example 4(75.2 mg) were mixed to give enriched mixtures 75:25 to give the title compound.
  • Example 6b l-(4-Fluoro-2-methvI-phenyl)-piperazine-2-carboxylic acid H-(3,5-dichloro-phenyl)- ethyll-methylamide (6b) (diastereoisomer B)
  • Example 7 l-(4-Fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid [l-(3,5-dichIoro-phenvD- ethvn-methylamide (7a) (diastereoisomer 1) l-(4-Fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid [l-(3,5-dichloro-phenyI)- ethyll-methylamide (7b) (diastereoisomer 2 " )
  • the mixture was filtered through a pad of celite, which was washed with further EtOH.
  • Example 12 l-(4-Fluoro-2-methyI-phenyl)-piperazine-2-carboxylic acid (3,5-dibromo-benzyl)- methylamide hydrochloride (12a - enantiomer 1) l-(4-FIuoro-2-methyl-phenyl)-piperazine-2-carboxylic acid (3,5-dibromo-benzvD- methylamide hydrochloride (12b - enantiomer 2)
  • Example 10 The compound of Example 10 (120 mg) was dissolved in a 5% sodium hydrogen carbonate solution (10 mL) and extracted with AcOEt (15 mL). The organic layer was dried and concentrated in vacuo to give l-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid
  • Enantiomer 1 (36.4 mg) was dissolved in anhydrous Et2O (1 mL) and treated at -10°C with hydrochloric acid (IM in Et2O - 87.5 ⁇ L). The mixture was stirred at 0°C for 15 minutes, then concentrated in vacuo. The residue was triturated with pentane (2 x 1 mL) to give the title compound 12a (26.2 mg) as a white solid.
  • Example 12b Enantiomer 2 (37.8 mg) was dissolved in anhydrous Et2O (1 mL) and treated at 0°C with hydrochloric acid (IM in Et2O - 90.8 ⁇ L). The mixture was stirred at 0°C for 15 minutes, then concentrated in vacuo. The residue was triturated with pentane (2 x 1 mL) to give the title compound 12b (28.1 mg) as a white solid.
  • (+/-) l-(4-Fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid (3-chloro-4-fluoro- benzvD-methylamide hydrochloride TFA (1.25 mL) was added to a solution of intermediate 24 (43 mg) in anhydrous DCM (4 mL) previously cooled to 0°C under a Nitrogen atmosphere. The solution was stirred at 0°C for 20 hours, then it was concentrated in vacuo. The residue was diluted with a saturated sodium carbonate solution and extracted twice with AcOEt.
  • (+/-) l-(2,4-Difluoro-phenyl)-piperazine-2-carboxyIic acid (3,5-bis-trifl ⁇ oromethvI- benzvD-methylamide hydrochloride TFA (1 mL) was dropped into a solution of intermediate 35 (115 mg) in anhydrous DCM (9 mL) previously cooled to 0°C under a Nitrogen atmosphere. The solution was stirred at 0°C overnight, then it was concentrated in vacuo. The residue was diluted with AcOEt and washed with a saturated potassium carbonate solution. The aqueous layer was extracted with further AcOEt.
  • (+/-) l-(2,4,6-Trifluoro-phenyl)-piperazine-2-carboxylic acid (3,5-bis-trifluoromethyl- benzvD-methylamide hydrochloride
  • TFA 0.5 mL
  • a solution of intermediate 43 31 mg
  • anhydrous DCM 5 mL
  • TFA 0.2 mL
  • the solution was stirred at 0°C for further 2 hours.
  • the solution was concentrated in vacuo.
  • the residue was diluted with AcOEt and washed with a saturated potassium carbonate solution.
  • the aqueous layer was extracted with further AcOEt.
  • (+/-) l-(4-Fluoro-phenyl)-piperazine-2-carboxylic acid (3,5-bis-triflnoromethyl-benzyl)- methylamide hydrochloride A mixture of intermediate 47 (77 mg) in EtOH (10 mL) containing 2 drops of glacial acetic acid and 10% palladium on carbon (20 mg) was stirred under hydrogen at 6 atmospheres for 22 hours. The mixture was filtered through a pad of celite.
  • Example 2a (1 g) was suspended in MeOH (12 mL) and heated to 65-70°C until completed dissolution. The mixture was cooled to 50°C then it was filtered and concentrated to 10 mL.
  • the active ingredient is blended with the other excipients.
  • the blend can be used to fill gelatin capsules or compressed to form tablets using appropriate punches.
  • the tablets can be coated using conventional techniques and coatings.
  • the active ingredient is blended with microcrystalline cellulose and croscarmellose sodium. Magnesium stearate is then added to the previuos blend. The mixture thus obtained can be compressed using appropriate punches and the tablets coated using conventional techniques and coatings.
  • the formulation may be packed in glass vials or plastic bag.
  • the affinity of the compound of the invention for NKj receptor was determined using the NKi receptor binding affinity method measuring in vitro by the compounds' ability to displace [3H] - substance P (SP) from recombinant human NKj receptors expressed in Chinese Hamster Ovary (CHO) cell membranes.
  • SP displace [3H] - substance P
  • the affinity values are expressed as negative logarithm of the inhibition constant (Ki) of displacer ligands (pKi).
  • the pKi values obtained as the average of at least two determinations with representative compounds of the invention are within the range of 9.40 to 8.00.
  • the affinity of the compound of the invention for serotonin transporter was determined using the hSERT binding affinity method and measuring in vitro the compounds' ability to displace [ 3 H] - Imipramine from recombinant human serotonin transporter expressed in Human Embryonic Kidney HEK293 cell membranes.
  • the affinity values are expressed as negative logarithm of the inhibition constant (Ki) of displacer ligands (pKi).
  • Ki inhibition constant
  • pKi displacer ligands

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Abstract

L'invention porte sur des dérivés de la pipérazine de formule (I) dans laquelle: R représente halogène, C1-4 alkyle, trifluorométhoxy ou trifluorométhyle; R1 est trifluorométhyle, C1-4 alkyle, C1-4 alkoxy, halogène ou trifluorométhoxy; R2 est hydrogène, C1-4 alkyle ou C2-6 alcényle; R3 représente hydrogène ou C1-4 alkyle; n et m sont indépendamment 0 ou un entier de 1 à 3; sur leurs sels et solvates pharmacocompatibles, sur leur procédé de préparation, et sur leur utilisation dans le traitement d'états médiés par les tachykinines et/ou par inhibition sélective de la protéine transporteuse de recapture de la sérotonine.
PCT/EP2002/009066 2001-08-14 2002-08-13 1-arylpiperazines substituees en 2 antagonistes de la tachykinine et/ou des inhibiteurs de la recapture de la serotonine Ceased WO2003015784A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE60206781T DE60206781T2 (de) 2001-08-14 2002-08-13 2-substituierte 1-arylpiperazine als tachykinin-antagonisten und/oder serotonin-wiederaufnahme-hemmer
EP02794786A EP1423117B1 (fr) 2001-08-14 2002-08-13 1-arylpiperazines substituees en 2 antagonistes de la tachykinine et/ou des inhibiteurs de la recapture de la serotonine
US10/486,479 US7214680B2 (en) 2001-08-14 2002-08-13 2-substituted 1-arylpiperazines as tachykinin antagonists and/or serotonin reuptake inhibitors
JP2003520743A JP2005502655A (ja) 2001-08-14 2002-08-13 タキキニンアンタゴニストおよび／またはセロトニン再摂取阻害剤としての２−置換１−アリールピペラジン
AT02794786T ATE306924T1 (de) 2001-08-14 2002-08-13 2-substituierte 1-arylpiperazine als tachykinin- antagonisten und/oder serotonin-wiederaufnahme- hemmer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0119797.9 2001-08-14
GBGB0119797.9A GB0119797D0 (en) 2001-08-14 2001-08-14 Chemical compounds

Publications (1)

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WO2003015784A1 true WO2003015784A1 (fr) 2003-02-27

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PCT/EP2002/009066 Ceased WO2003015784A1 (fr) 2001-08-14 2002-08-13 1-arylpiperazines substituees en 2 antagonistes de la tachykinine et/ou des inhibiteurs de la recapture de la serotonine

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US (1) US7214680B2 (fr)
EP (1) EP1423117B1 (fr)
JP (1) JP2005502655A (fr)
AR (1) AR035110A1 (fr)
AT (1) ATE306924T1 (fr)
DE (1) DE60206781T2 (fr)
ES (1) ES2247408T3 (fr)
GB (1) GB0119797D0 (fr)
WO (1) WO2003015784A1 (fr)

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WO2005037803A1 (fr) * 2003-10-09 2005-04-28 Speedel Experimenta Ag Composes organiques
WO2007063009A1 (fr) * 2005-12-01 2007-06-07 F. Hoffmann-La Roche Ag Inhibiteurs du transporteur de serotonine (sert)
JPWO2005095327A1 (ja) * 2004-03-31 2008-02-21 味の素株式会社 アニリン誘導体
WO2008019971A3 (fr) * 2006-08-17 2008-05-02 Hoffmann La Roche Dérivés d'arylpipérazine et leurs utilisations
WO2009022731A1 (fr) 2007-08-10 2009-02-19 Nippon Chemiphar Co., Ltd. Antagoniste de récepteur p2x4
US7872022B2 (en) 2006-04-03 2011-01-18 Hoffmann-La Roche Inc. Serotonin transporter (SERT) inhibitors for the treatment of depression and anxiety
US7998963B2 (en) 2008-02-15 2011-08-16 Roche Palo Alto Llc Arylpiperazine derivatives and uses thereof
WO2012124775A1 (fr) * 2011-03-16 2012-09-20 田辺三菱製薬株式会社 Composé hétérocyclique saturé contenant de l'azote
WO2013004766A1 (fr) 2011-07-04 2013-01-10 Ferrari Giulio Antagonistes des récepteurs nk-1 pour traiter une néovascularisation cornéenne
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WO2004089915A1 (fr) * 2003-04-10 2004-10-21 Warner-Lambert Company Llc Derives de piperazine agissant comme inhibiteurs de la renine
WO2004091617A1 (fr) * 2003-04-17 2004-10-28 Glaxo Group Limited Combinaison de paroxetine et de 2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl-benzyl)-(2s-phenyl-piperidin-3s-yl)-amine dans le traitement de la depression et/ou de l'anxiete
WO2004091624A1 (fr) * 2003-04-17 2004-10-28 Glaxo Group Limited Combinaison comprenant paroxetine et 2- (s) - (4-fluoro-2-methyl-phenyl) -piperazine-1-acide carboxylique [1- (r)- (3,5-bis-trifluoro-2-methyl-phenyl) -ethyl]-methyl amide destinee au traitement de la depression et/ou de l'anxiete
WO2005037803A1 (fr) * 2003-10-09 2005-04-28 Speedel Experimenta Ag Composes organiques
EP1736465A4 (fr) * 2004-03-31 2009-06-17 Ajinomoto Kk Dérivés d'aniline
JP4775259B2 (ja) * 2004-03-31 2011-09-21 味の素株式会社 アニリン誘導体
JPWO2005095327A1 (ja) * 2004-03-31 2008-02-21 味の素株式会社 アニリン誘導体
US7879863B2 (en) 2004-03-31 2011-02-01 Ajinomoto Co., Inc. Aniline derivatives
WO2007063009A1 (fr) * 2005-12-01 2007-06-07 F. Hoffmann-La Roche Ag Inhibiteurs du transporteur de serotonine (sert)
CN101316816B (zh) * 2005-12-01 2011-07-27 弗·哈夫曼-拉罗切有限公司 5-羟色胺转运体(sert)抑制剂
KR101091376B1 (ko) 2005-12-01 2011-12-07 에프. 호프만-라 로슈 아게 세로토닌 수송체(ｓｅｒｔ) 억제제
US7872022B2 (en) 2006-04-03 2011-01-18 Hoffmann-La Roche Inc. Serotonin transporter (SERT) inhibitors for the treatment of depression and anxiety
US8580821B2 (en) 2006-04-03 2013-11-12 Hoffmann-La Roche Inc. Serotonin transporter (SERT) inhibitors for the treatment of depression and anxiety
US7754721B2 (en) 2006-08-17 2010-07-13 Roche Palo Alto Llc Arylpiperazine derivatives and uses thereof
WO2008019971A3 (fr) * 2006-08-17 2008-05-02 Hoffmann La Roche Dérivés d'arylpipérazine et leurs utilisations
KR101077423B1 (ko) 2006-08-17 2011-10-26 에프. 호프만-라 로슈 아게 아릴피페라진 유도체 및 그의 용도
CN101501008B (zh) * 2006-08-17 2011-12-07 弗·哈夫曼-拉罗切有限公司 芳基哌嗪衍生物及其用途
WO2009022731A1 (fr) 2007-08-10 2009-02-19 Nippon Chemiphar Co., Ltd. Antagoniste de récepteur p2x4
US7998963B2 (en) 2008-02-15 2011-08-16 Roche Palo Alto Llc Arylpiperazine derivatives and uses thereof
WO2012124775A1 (fr) * 2011-03-16 2012-09-20 田辺三菱製薬株式会社 Composé hétérocyclique saturé contenant de l'azote
KR20130133294A (ko) * 2011-03-16 2013-12-06 미쓰비시 타나베 파마 코퍼레이션 질소-함유 포화 헤테로시클릭 화합물
CN103562191A (zh) * 2011-03-16 2014-02-05 上海医药集团股份有限公司 含氮的饱和杂环化合物
US9278944B2 (en) 2011-03-16 2016-03-08 Mitsubishi Tanabe Pharma Corporation Nitrogen-containing saturated heterocyclic compound
CN103562191B (zh) * 2011-03-16 2016-03-30 上海医药集团股份有限公司 含氮的饱和杂环化合物
KR101651722B1 (ko) 2011-03-16 2016-08-26 미쓰비시 타나베 파마 코퍼레이션 질소-함유 포화 헤테로시클릭 화합물
US10155731B2 (en) 2011-03-16 2018-12-18 Mitsubishi Tanabe Pharma Corporation Nitrogen-containing saturated heterocyclic compound
WO2013004766A1 (fr) 2011-07-04 2013-01-10 Ferrari Giulio Antagonistes des récepteurs nk-1 pour traiter une néovascularisation cornéenne
US11053202B2 (en) 2016-09-21 2021-07-06 Vectus Biosystems Limited Compositions for the treatment of hypertension and/or fibrosis
US11834417B2 (en) 2016-09-21 2023-12-05 Vectus Biosystems Limited Compositions for the treatment of hypertension and/or fibrosis

Also Published As

Publication number Publication date
US7214680B2 (en) 2007-05-08
EP1423117A1 (fr) 2004-06-02
JP2005502655A (ja) 2005-01-27
DE60206781T2 (de) 2006-06-01
ATE306924T1 (de) 2005-11-15
EP1423117B1 (fr) 2005-10-19
DE60206781D1 (de) 2006-03-02
AR035110A1 (es) 2004-04-14
US20040242592A1 (en) 2004-12-02
ES2247408T3 (es) 2006-03-01
GB0119797D0 (en) 2001-10-03

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